Pyrrolidino-2, 6-dimethyl anilide salt of 8-[2&#39;-methoxy-3&#39;-(7-theophyllinyl mercuri)] propyl-coumarin-3-carboxylic acid



United States Patent" Albert Schlesinger, Jackson Heights, and Samuel M. Gordon, Forest Hills, N. Y., assignors to Endo Laboratories Inc., Richmond Hill, N. Y., a corporation of New York- No Drawing. Application Mara. 21, 1956,

Serial No.574,092

Claims. 01. 260- 242 j This invention relates to novel addition salts-of i2" methoxy-3'-(7-theophyllinyl mercuri)] propyl-coumarin- 3-carboxylic acid having the structural formula:

The alkali metal salts of the above mentioned compound, designated as mercumatilin by the American Medical Association (New and Nonoflicial Remedies, 1954, page 350) are particularly etfective as diuretics. They may be administered per os or by intravenous or intramuscular injection.

It is known that metal compounds sometimes, and mercuri-derivatives in particular, show side effects when administered intramuscularly, and especially upon subcutaneous application. These side elfects are evidenced by sensation of pain or allergic manifestation. In general, mercurial diuretics are not well tolerated when administered by the subcutaneous route.

It is among the principal objects of this invention to provide a novel salt of mercumatilin which is featured by the absence of side reactions such as pain or allergic manifestations when administered intramuscularly and is well tolerated when introduced via the subcutaneous route.

An even more particular object of this invention is to provide a novel salt of mercumatilin prepared from a novel base which possesses local anaesthetic characteristics, more particularly the pyrrolidino-aceto-Z,6-dimethylanilide of the following formula:

(5H CHI-CH2 The known local anaesthetics are in general esters which are easily hydrolyzed in aqueous solution; a characteristic which appears in some of the salts thus formed with the aforesaid mercuri-theophylline complex (mercumatilin).

The known local anesthetics of more stable structure, such as ketones or ethers, however do not have the fastacting and lasting effect which is desired, or are too toxic or do not possess the very important feature of this invention, to wit, good aqueous solubility of the salt.

.. Patented .Nov. ,19, 1957 The new pyrrolidino-aceto-Z,6-dimethylanilide, is a local anesthetic with fast and lasting action, of low tox: icity and forms an excellent water soluble salt with mercumatilin having the formula:

solution of about pH=6.87. The solution so prepared well tolerated by intramuscular as injection. V I

The pyrrolidino-aceto-2,6-dimethylanilide is'prepared by the reaction of chloro-acetoJ-2, 6-dimetliylanilide with an excess of pyrrolidine. v a

The following examples are illustrative of the compounds of this invention:

EXAMPLE 1 Pyrrolidino aceto-2,6-dimethyl anilide 38 grams of chloro-acetyl-2,6-dimethylanilide and 45 grams of pyrrolidine in 300 cc. of anhydrous benzene are refluxed for five hours. The solution is cooled and 200 cc. of water and 50 cc. of concentrated hydrochloric acid are added, and shaken in a separatory funnel. The water solution is then alkalized with 70 cc. sodium hydroxide solution (40 percent) and the new base is extracted with ether. The ethereal solution is dried over anhydrous KaCOs, filtered and evaporated. The residue is dissolved in cc. of hexane by heating on the water bath, then cooled in an ice bath. The base crystallizes and is filtered on a Buchner funnel, washed with pentane and dried in a desiccator.

Yield-=36 grams=82 percent, M. P. 83 C. HCl salt, crystallized from isopropanol M. P. 205 C. Molecular weight C14H20N20.HC1 268.77. Calculated: 01: 13.19 percent; found: 01:13.24 percent.

EXAMPLE 2 Solution of 8-[2'-m'eth0xy-3'-(7-theophyllinyl mercuri)] propyl c0umarin-3-carb0xylic acid-pyrrolidino-aceto- 2,6-dimethylanilide 8.2 grams of theophylline U. S. P. are suspended in cc. of water and with stirring 10 grams pyrrolidinoaceto-2,6-dimethylanilide (the product of Example 1) are added thereto. After stirring for ten minutes, 19.2 grams of 8-(2'-methoxy-3-hydroxy-mercuri-propyl) coumarin- 3-carboxylic acid are added in small portions and then the mixture is heated with stirring until 70 C. The solution is cooled to room temperature and distilled water is added to bring the volume to 200 cc. pH=6.9.

This solution is aseptically filtered and filled in ampules for administration by injection. 1 cc. of the solution contains 40 mg. of mercury. The solutions are stable and are tolerated without pain.

EXAMPLE 3 Dry salt of Example 2 20 cc. of the solution of Example 2 are evaporated under vacuum and the residue dissolved in hot iso.

well I assubcutaneous propanol. Upon the addition of ether to the cooled isopropanol solution, the salt of pyrrolidino-aceto-2,6-dimethylanilide mercumallylic acid precipitates. It is filtered on a Buchner filter and dried in a desiccator.

It has a melting point of 150 C. It is readily soluble in 5 water. Molecular weight of C35H40NsOsHg=873.33. Calculated: Hg=22.97 percent; found: Hg=22.8.5 percent.

It will be understood that the foregoing description of the invention and the examples set forth are merely illustrative of the principles thereof. Accordingly, the appended claims are to he construed as defining the invention within the full spirit and scope thereof.

We claim:

1. The pyrrolidino-aceto-2,G-dimethyl-anilide salt of mercumallylic acid having the formula:

2. Method of manufacturing an aqueous solution of the salt of claim 1 which comprises dissolving equivalent amounts of theophylline, pyrrolidino-aceto-Z,6-dimcthylanilide and 8 (2'-methoxy-3'-hydroxymercuri-propyl)- coumarin-3-carboxylic acid in water.

3. The method of claim 2, wherein the solution is heated to approximately 70 C., and then cooled; and water added to bring the pH to approximately neutrality.

4. Method of isolating the salt of claim 1 which comprises evaporating the solution of claim 3 under vacuum, and crystallizingv the residue thus obtained.

5. Method in accordance with claim 4 wherein the crystallization is carried out by taking the residue up in is-opropanol and ether.

References Cited in the file of this patent UNITED STATES PATENTS 2,480,224 Cusic et a1 Aug. 30, 1949 2,576,349 Lehman Nov. 27, 1951 2,592,418 Halpern Apr. 8, 1952 2,605,267 Reid July 29, 1952 

1. THE PYRROLIDINO-ACETO-2,6-DIMETHYL-ANILIDE SALT OF MERCUMALLYLIC ACID HAVING THE FORMULA: 